Acquired immunodeficiency syndrome (AIDS) is a degenerative disease of the immune system and central nervous system (CNS) resulting from infection of humans by HIV virus. AIDS is responsible for a rapidly growing fatality rate in the world population. At present, no cure has been found, and clinically approved drugs are limited in number. These drugs include nucleoside reverse transcriptase (RT) inhibitors such as 3xe2x80x2-azido-3xe2x80x2-deoxythymidine (AZT, Zidovudine), dideoxyinosine (ddI, Didanosine), dideoxycytidine (ddC, Zalcitabine), 2xe2x80x2, 3xe2x80x2-dideoxy-3xe2x80x2-thiacytidine (3TC, Lamivudine), and 2xe2x80x2, 3xe2x80x2-didehydro-3xe2x80x2-deoxythymidine (d4T, Stavudine), a non-nucleoside RT inhibitor (Niverapine), and protease inhibitors such as saquinavir (Inverase), ritonavir (Norvir), indinavir (Crixivan), and nelfinavir (Viracept). Nucleoside RT inhibitors generally have similar structures (2xe2x80x2, 3xe2x80x2-dideoxynucleosides) and act at an early stage in virus replication to inhibit provirus DNA synthesis (De Clercq, 1995, Journal of Medicinal Chemistry, 38:2491-2517). However, AZT, the recommended initial therapeutic agent, and the other nucleoside analogues have several limitations, including adverse side effects such as bone marrow depression and anemia (Gill et al., 1987, Annals of Internal Medicine, 107:502-505; Richman et al., 1987, New England Journal of Medicine, 317:192-197). Peripheral neuropathy is also a major and common side effect. AZT is rapidly eliminated from the plasma with a half-life of about one hour (Surbone et al., 1988, Annals of Internal Medicine, 108:534-540) and is quickly metabolized in the liver to its corresponding 5xe2x80x2-glucuronide, which is inactive.
Presently, only a small number of antiviral drugs are available for treatment of virus infections. A complication to the development of such drugs is that mutant strains of virus which are resistant to currently available antiviral drugs are developing at an alarming rate. Combinations of new drugs having unique modes of action are urgently needed to replace drugs that have lost their potency against viruses as a result of virus mutations. A further complication to the development of antiviral drugs is that development of viral resistance to available compounds is not the same in different body compartments and fluids. For example, evolution of drug resistance among HIV-1 clinical isolates is often discordant in blood and semen of HIV-1 positive males (Eron et al., 1998, AIDS 12:F181-F189).
Further, currently available drugs useful for antiviral therapy sometimes ineffectively penetrate the genital tract. This is a serious drawback to the use of these drugs to combat viruses which infect the genital tract. If an antiviral drug promotes development of resistance in the genital tract and the virus is commonly transmitted from this body site, the drug will rapidly become ineffective for treatment of the virus infection in the population at risk for transmission. Hence, drug-resistant mutants of certain viruses can be rapidly spread by sexual contact in the human population. It is known that viruses such as HIV, hepatitis B, hepatitis C, herpes simplex virus, cytomegalovirus, papilloma viruses, and many others are transmitted via sexual contact by both males and females. Thus, therapeutic drugs that fully suppress virus infections in the genital tract are a high public health priority.
Another limitation of presently available antiviral drugs is that rapid emergence of drug resistant mutant virus can lead to decreased sensitivity to the drug within a patient or within a patient population (Larder et al., 1989, Science, 243:1731-1734). Thus, the beneficial effects of drugs such as AZT are limited in duration.
The anti-HIV chemotherapy era which started a decade ago has recently made significant progress toward better control of HIV-1 infection by the introduction of protease inhibitors and the use of combinations of nucleoside and non-nucleoside RT inhibitors with protease inhibitors. Monotherapy (e.g. administration of a single drug) using a nucleoside or non-nucleoside RT inhibitor or a protease inhibitor is no longer a recommended form of therapy for treatment of a patient with a virus infection such as HIV-1 infection. Although combinations of AZT, 3TC, and a protease inhibitor have reduced virus load in the plasma of patients to below detectable levels (i.e. fewer than 200 copies of viral RNA per milliliter of plasma) with a concomitant increase in CD4+ cell count, some drug combinations have been associated with increased toxicity in a person receiving multiple drug therapies. Also, although reduction in virus burden in the plasma of patients to non-detectable levels achieved using some drug combinations is impressive, drug resistance is an escalating problem due to both use and misuse of drug therapy (De Clercq, 1995, Journal of Medicinal Chemistry, 38:2491-2517; Bartlett, 1996, Infectious Diseases in Clinical Practice, 5:172-179) and evolution of resistant mutants in blood and seminal fluids (Eron et al., 1998, AIDS, 12:F181-F189).
The pathogenic events in HIV disease have recently been reviewed by Fauci (1996, Nature {New Biology}, 384:529-534). The current understanding is that entry of HIV into cells varies with the virus strain and cell type. Primary infection of humans is associated with macrophage tropic (M-tropic) virus that utilize the CD4 receptor and a beta-chemokine co-receptor (CCR5) for entry into macrophages. As HIV infection progresses, the initial M-tropic viruses are usually replaced by T-tropic viruses that enter T-lymphocytes via the CD4 receptor and co-receptor CXCR4 (fusin). The viral determinant of cellular tropism maps to the gp 120 subunit of HIV-1 Env protein, particularly the 3rd variable region or V3 loop of gp120. Upon entry into these cells, HIV probably infects dendretic cells, which then carry the virus to CD4+ cells in the lymphoid organs. Infection is then established in the lymphoid organs and a burst of infectious virus seeds itself throughout the body, including the CNS, brain, and lymphoid tissues and sexual organs (e.g. testes). Current drugs used in therapies for HIV infection and AIDS noted above have a limited capacity and half-life for absorption from the stomach to the blood, accumulation into lymphoid organs, crossing the blood-brain barrier into the CNS, or entering the sexual organs (e.g. testes) to attack sanctuaries for HIV replication.
Synthetic phosphocholine lipid (PC lipid) analogues such as, for example, 1-decanamido-2-decyloxypropyl-3-phosphocholine (INK-11) have demonstrated a low incidence of unwanted side effects in mice such as reduction of bone marrow precursor cells and have exhibited high differential selectivity (i.e. the ratio of TC50 for cytotoxicity to EC50 for antiviral activity, DS=1342 for INK-11) in human leukocytes in cultured cells. At a dosage of 50 milligrams per kilogram of body weight per day for 21 days, INK-11 inhibited Friend leukemia virus-(FLV-) induced pathogenesis by 42% in infected mice, as indicated by significant activity against splenomegaly. The observation that use of INK-11 resulted in only moderate suppression against RT activity compared with AZT alone (42% vs 98%, respectively) suggests that INK-11 induces production of defective virus, similar to the effect achieved using other lipid compounds alone (Kucera, et al., 1990, AIDS Research and Human Retroviruses 6:491-501).
Other synthetic phospholipids which do not comprise a phosphocholine moiety (non-PC lipids) have been conjugated with antiviral chemotherapeutic agents. For example, thioether lipid-nucleoside conjugates have exhibited improved antineoplastic activity in tumor-bearing mice (Hong et al., 1990, Journal of Medicinal Chemistry 33:1380-1386). Also, natural phospholipids coupled to AZT or to dideoxynucleosides (ddT, ddC) have proven to be markedly active against HIV by inhibiting viral RT activity (Steim et al., 1990, Biochemical and Biophysical Research Communications 171:451-457; Hostetler et al., 1990, Journal of Biological Chemistry 265:6112-6117; Hostetler et al., 1991, Journal of Biological Chemistry 266:11714-11717). Studies of phospholipid antiviral efficacy have also included chemically conjugating AZT or ddI, through a phosphate-ester bond, to selected synthetic phosphatidic acid lipid analogues (Piantadosi et al., 1991, Journal of Medicinal Chemistry 34:1408-1414). Synthetic phosphate-ester linked lipid-nucleoside conjugates were found to be markedly active against infectious HIV-1 production in both acutely- and persistently-infected cells, and were 5- to 10-fold less cytotoxic compared with AZT alone (Piantadosi et al., 1991, Journal of Medicinal Chemistry 34:1408-1414). Results of preliminary studies indicated that synthetic lipid-AZT conjugates block reactivity of HIV-1-induced gp160/gp120 proteins with specific monoclonal antibodies on the surface of infected and treated cells and on the surface of treated HIV-1 particles, as measured by flow cytometry. These conjugate compounds also caused inhibition of HIV-1-induced cell fusion (Kucera et al., 1992, In: Novel Membrane Interactive Ether Lipids With Anti-Human Immunodeficiency Virus Activity, Aloia et al., eds., Membrane Interactions of HIV, pp.329-350; Krugner-Higby et al., 1995, AIDS Research and Human Retroviruses 11:705-712). However, these phosphate ester-linked lipid-AZT conjugates (non-PC lipid-AZT conjugates) were not very active against AZT-resistant clinical isolates of HIV-1. Moreover, after intracellular metabolism of the conjugate with resulting release of AZT-monophosphate, the lipid moiety exhibited only moderate to non-detectable antiviral activity (Piantadosi et al., 1991, Journal of Medicinal Chemistry 34:1408-1414).
As with the antiviral agents, the development of anticancer agents for treating cancer effectively has also been problematic. Barriers such as cellular mechanisms of anticancer drug resistance, overcoming the blood-brain barrier to provide adequate delivery of drug to the brain and CNS, inadequate uptake of drug by lymphoid and hematopoietic tissues, toxicity, achieving oral bioavailability, overcoming short drug half-life, and preventing extracellular metabolism of the anticancer agent are faced by the skilled artisan.
In order to improve bioavailability to CNS and brain tissue, nucleoside analogues have been encapsulated in liposomes or used with modifying agents to disrupt the blood-brain barrier (Braekman, et al., 1997, Proc. Amer. Soc. for Clinical Oncology, Abstract #810). Implantable devices have been used to provide more sustained drug delivery to increase the pharmacokinetics of anticancer agents (Del Pan, et al., 1997, Proc. Amer. Soc. for Clinical Oncology, Abstract #1384). Additionally, attempts to improve the efficacy of nucleoside analogues in cancer therapy have included the use of multidrug combinations and high-dose nucleoside analogue therapy (Capizzi, 1996, Investigational New Drugs 14:249-256). None of these methods have adequately overcome the problems discussed above with regard to anticancer agents.
Another attempt to circumvent the problems associated with conventional nucleoside analogue cancer therapy has been the conjugation of these molecules to phospholipids. Thus far, the conjugation of nucleoside analogues to phospholipid molecules has focused on ara-C and a limited number of diacyl, alkylacyl and thioether phospholipids (Hong, 1990, Cancer Res. 50:4401-4406). Although these conjugates have shown efficacy in the treatment of hematologic malignancies, these drugs must be administered intraperitoneally or intravenously and do not overcome the problems discussed above regarding anticancer agents. These conjugates are degraded by phospholipase A and phospholipase B extracellularly and do not provide the option of oral administration.
Despite the promising attributes of compounds such as PC lipids, and non-PC lipid-nucleoside analogue conjugates, currently available antiviral and anticancer agents such as nucleoside analogues and anti-HIV nucleoside drugs have severe inherent limitations. Although such drugs are capable of delaying the onset of symptoms of virus infection and extending survival time for patients, new compounds having the attributes of increased tolerability, potency, and selectivity against specific viruses, differential mechanisms of action, ability to cross the blood-brain barrier, and freedom from myelosuppressive side effects are urgently needed for improved treatment of virus infections. Also, new antiviral and anticancer compounds are needed which more effectively combat cancers or target multiple aspects of the virus life cycle, which facilitate delivery of an anticancer agent to cells and tissues not normally accessible to anticancer agents (e.g. CNS and lymphoid tissues), which combine lipophilic (e.g. phospholipid) and antiretroviral or anticancer agents within the same molecule (e.g. conjugate compounds) in order to yield a drug with a more sustained antiviral or anticancer effect, which decrease the rate of emergence of drug-resistant virus strains, and which inhibit virus replication in a wider range of cellular or tissue reservoirs of virus infection. The present invention satisfies these needs.
The invention includes a compound having the structure of Formula I: 
wherein
n and m are each independently 0 or 1, but n and m are not both 0;
R1 is (C1-C16)alkyl, branched alkyl, alkenyl or alkynyl if n is 0 and (C1-C16)alkylene, branched alkyl, alkenyl or alkynyl if m is 1;
R2 is (C1-C16)alkyl, branched alkyl, alkenyl or alkynyl if m is 0 and (C1-C16) alkylene, branched alkyl, alkenyl or alkyhyl if m is 1;
R3, R4and R5 are each independently (C1-C8)alkylene;
R6, R7 and R8 are each independently (C1-C16)alkyl;
X1 and X2 are each independently S, O, NHCxe2x95x90O, OCxe2x95x90O or NH;
X3 is O or S;
E1 is H, S, halo or N3;
Z1 is H, S, or halo; or E1 and Z1 together are a covalent bond;
E2 is H, S, halo, or N3;
Z2 is H, S, or halo; or E2 and Z2 together are a covalent bond;
D1 and D2 are each independently selected from the group consisting of purine, pyrimidine, adenine, thymine, cytosine, guanine, hypoxanthine, inosine, uracil and ring modifications thereof, including O, N, and S substitutions, and
wherein, each alkyl, alkylene, branched alkyl, alkenyl, alkynyl, adenine, thymine, cytosine, guanine, pyrimidine, purine, hypoxanthine, inosine and uracil of R1, R2, R3, R4, R5, R6, R7, R8, D1, and D2 can, optionally, be substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, nitro, trifluoromethyl, (C1-C8)alkyl, (C1-C8)alkoxy, aryl, and N(Ra)(Rb) wherein Ra and Rb are each independently selected from the group consisting of H and (C1-C8)alkyl.
In one aspect, the compound is present in an amount effective to inhibit virus replication in a mammal.
In another aspect, R1 is (C6-C16)alkyl if n is 0 or xe2x80x94CHxe2x95x90CHxe2x80x94 if n is 1.
In yet another aspect, R2 is (C6-C16)alkyl if m is 0 or xe2x80x94CHxe2x95x90CHxe2x80x94 if m is 1.
In a further aspect, R3 is xe2x80x94CH2CH2xe2x80x94.
In one embodiment, R4 is xe2x80x94CH2xe2x80x94.
In another embodiment, R5 is xe2x80x94CH2xe2x80x94.
In yet another embodiment, R6, R7 and R8 are each xe2x80x94CH3.
In one aspect, X1 is S, NHCxe2x95x90O, xe2x80x94NHxe2x80x94 or O.
In another aspect, X2 is S, NHCxe2x95x90O or O.
In a further aspect, X3 is O or S.
In another aspect, E1 is N3, S or H.
In one embodiment, Z1 is H or S.
In another embodiment, E2 is N3, S or H.
In a further embodiment, Z2 is H or S.
In one aspect, n is 0 and m is 1.
In another aspect, n is 1 and m is 0.
In yet another aspect, D1 is selected from the group consisting of cytosine, guanine, inosine and thymine.
In a further aspect, D2 is selected from the group consisting of cytosine, guanine, inosine and thymine.
In another aspect, the compound is in the form of a pharmaceutically acceptable salt.
In one embodiment, the compound is present in an amount effective to inhibit virus replication in a mammal.
In a preferred embodiment, R1 is (C6-C16)alkyl, branched alkyl, alkenyl or alkynyl; R2 is (C4-C12)alkylene; R3 is xe2x80x94CH2CH2xe2x80x94; R5 is xe2x80x94CH2xe2x80x94; R6, R7 and R8 are each CH3; X1 and X2 are each independently S, O or NHCxe2x95x90O; E2 is H or N3; D2 is selected from the group consisting of thymine, cytosine, guanine and inosine, and wherein each alkyl, branched alkyl, alkylene, alkenyl, alkynyl, thymine, cytosine, guanine, and inosine of R1, R2, R3, R5, R6,R7, R8, and D2 can, optionally, be substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, nitro, trifluoromethyl, (C1-C8)alkyl, (C1-C8)alkoxy, aryl, and N(Ra)(Rb), wherein Ra and Rb are each independently selected from the group consisting of H and (C1-C8)alkyl.
The invention also includes a method of treating a virus infection in a mammal. The method comprises administering to the mammal, in an amount effective to treat the infection, a compound having the structure of Formula I: 
wherein,
n and m are each independently 0 or 1, but n and m are not both 0;
R1 is (C1-C16)alkyl, branched alkyl, alkenyl or alkynyl if n is 0 and (C1-C16)alkylene, branched alkyl, alkenyl or alkynyl if n is 1;
R2 is (C1-C16)alkyl, branched alkyl, alkenyl or alkynyl if m is 0 and (C1-C16) alkylene, branched alkyl, alkenyl or alkynyl if m is 1;
R3, R4 and R5 are each independently (C1-C8)alkylene;
R6, R7 and R8 are each independently (C1-C8)alkyl;
X1 and X2 are each independently S, O, NHCxe2x95x90O, OCxe2x95x90O or NH;
X3 is O or S;
E1 is H, S, halo or N3;
Z1 is H, S, or halo; or E1 and Z1 together are a covalent bond;
E2is H, S, halo, or N3;
Z2 is H, S, or halo; or E2 and Z2 together are a covalent bond;
D1 and D2 are each independently selected from the group consisting of purine, pyrimidine, adenine, thymine, cytosine, guanine, hypoxanthine, inosine, uracil and ring modifications thereof, including O, N, and S substitutions, and
wherein, each alkyl, alkylene, branched alkyl, alkenyl, alkynyl, adenine, thymine, cytosine, guanine, pyrimidine, purine, hypoxanthine, inosine and uracil of R1, R2, R3, R4, R5, R6, R7, R8, D1, and D2 can, optionally, be substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, nitro, trifluoromethyl, (C1-C8)alkyl, (C1-C8)alkoxy, aryl, and N(Ra)(Rb) wherein Ra and Rb are each independently selected from the group consisting of H and (C1-C8)alkyl.
In one aspect, R1 is (C8-C12)alkyl if n is 0 and xe2x80x94CH2CH2xe2x80x94 if n is 1.
In another aspect, R2 is (C8-C12)alkyl if m is 0 and xe2x80x94CH2CH2xe2x80x94 if m is 1.
In yet another aspect, R3 is xe2x80x94CH2CH2xe2x80x94.
In one embodiment, R4 is xe2x80x94CH2xe2x80x94.
In another embodiment, R5 is xe2x80x94CH2xe2x80x94.
In a further embodiment, R6, R7 and R8 are each xe2x80x94CH3.
In another embodiment, X1 is S or O.
In one aspect, X2 is S or O.
In another aspect, X3 is O.
In a further aspect, E1 is N3 or H.
In a still further aspect, Z1 is H.
In one embodiment, E2 is N3 or H.
In another embodiment, Z2 is H.
In yet another embodiment, n is 0 and m is 1.
In one aspect, n is 1 and m is 0.
In another aspect, D1 is selected from the group consisting of cytosine, guanine, inosine, and thymine.
In a further aspect, D2 is selected from the group consisting of cytosine, guanine, inosine, and thymine.
In a still further aspect, the virus infection is an infection by a virus selected from the group consisting of HIV, hepatitis virus, and a herpes virus.
In one embodiment, the HIV is selected from the group consisting of HIV-1 and HIV-2.
Preferably, the hepatitis virus is selected from the group consisting of hepatitis A, hepatitis B, hepatitis C, hepatitis D, and hepatitis E viruses.
Preferably, the herpes virus is selected from the group consisting of herpes simplex virus type 1, herpes simplex virus type 2, varicella-zoster virus, cytomegalovirus, Epstein Barr virus, human herpes virus type 6, human herpes virus type 7, and human herpes virus type 8.
In a preferred aspect, R1 is (C6-C16)alkyl, branched alkyl, alkenyl or alkynyl; R2 is (C4-C12)alkylene; R3 is xe2x80x94CH2CH2xe2x80x94; R5 is xe2x80x94CH2xe2x80x94; R6, R7 and R8 are each CH3; X1 and X2 are each independently S, O or NHCxe2x95x90O; E2 is H or N3; D2 is selected from the group consisting of thymine, cytosine, guanine and inosine, and wherein each alkyl, branched alkyl, alkylene, alkenyl, alkynyl, thymine, cytosine, guanine, and inosine of R1, R2, R3, R5, R6,R7, R8, and D2 can, optionally, be substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, nitro, trifluoromethyl, (C1-C8)alkyl, (C1-C8)alkoxy, aryl, and N(Ra)(Rb), wherein Ra and Rb are each independently selected from the group consisting of H and (C1-C8)alkyl.
In one aspect, a pharmaceutically acceptable salt of the compound is administered to the mammal.
Preferably, the mammal is a human.
The invention also includes a method of inhibiting virus replication in a cell. The method comprises administering to the cell a compound of Formula I in an amount effective to inhibit virus replication in the cell.
The invention includes a pharmaceutical composition comprising a compound of Formula I in combination with a pharmaceutically acceptable carrier.
In one aspect, the compound is present in an amount effective to inhibit virus replication in a mammal.
In another aspect, the compound is present in an amount effective to inhibit virus replication in a mammal.
The invention also includes a kit for treatment of a viral infection in a mammal. The kit comprises a) a composition selected from the group consisting of a compound of Formula I, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising a compound of Formula I, and b) an instructional material.
The invention also includes a kit for inhibition of virus replication in a cell. The kit comprises a) a composition selected from the group consisting of a compound of Formula I, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising a compound of Formula I, and b) an instructional material.
The invention also includes a compound having the structure of Formula III: 
wherein,
R11 is (C1-C16)alkyl, branched alkyl, alkenyl or alkynyl;
R12 is (C1-C16)alkyl, branched alkyl, alkenyl or alkynyl;
X11 is O, S, or NHCxe2x95x90O;
X12 is O, S, or NHCxe2x95x90O;
X13 is O or S;
n is 0, 1 or 2, and
R13 is a therapeutic agent,
wherein, each alkyl, branched alkyl, alkenyl, alkynyl, adenine, thymine, cytosine, guanine, pyrimidine, purine, hypoxanthine, inosine and uracil of R11, R12, and R13 can, optionally, be substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, nitro, trifluoromethyl, (C1-C8)alkyl, (C1-C8)alkoxy, aryl, and N(Ra)(Rb) wherein Ra and Rb are each independently selected from the group consisting of H and (C1-C8) alkyl, and
wherein, if n is 1 or 2, the compound is a phospholipase C substrate and is not a phospholipase A substrate, and
further wherein, if n is 1 or 2, the compound is converted to an alkyl lipid and a moiety selected from the group consisting of a nucleoside monophosphate and a nucleoside analogue monophosphate intracellularly in a mammal, and is not converted to an alkyl lipid and a moiety selected from the group consisting of a nucleoside monophosphate and a nucleoside analogue monophosphate extracellularly in a mammal.
In a preferred embodiment, R11 is a C12 alkyl, branched alkyl, alkenyl or alkynyl; R12 is C8H16 alkyl or branched alkyl; n=1, and R13 is an anticancer agent selected from the group consisting of gemcitabine, ara-C, 5-azacytidine, cladribine, fluclarabine, fluorodeoxyuridine, cytosine arabinoside and 6-mercaptopurine, wherein the phosphorus atom of the phosphate moiety is covalently linked in a phosphate ester likage to the oxygen atom of the 5xe2x80x2 hydroxyl group of a sugar moiety of R13.
The invention also includes a compound having the structure of Formula IV: 
wherein,
R21 is (C6 to C16)alkyl, branched alkyl, alkenyl, or alkynyl;
R22 is (C1-C12)alkyl, branched alkyl, alkenyl, or alkynyl;
X21 is O, S, or NHCxe2x95x90O;
X22 is O, S, or NHCxe2x95x90O;
X23 is O or S;
n is 1 or 2;
R23 is a therapeutic agent, and
wherein, each alkyl, branched alkyl, alkenyl, alkynyl, adenine, thymine, cytosine, guanine, pyrimidine, purine, hypoxanthine, inosine and uracil of R21, R22, and R23 can, optionally, be substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, nitro, trifluoromethyl, (C1-C8)alkyl, (C1-C8)alkoxy, aryl, and N(Ra)(Rb) wherein Ra and Rb are each independently selected from the group consisting of H and (C1-C8) alkyl.
In a preferred aspect, R21 is C12 alkyl; R22 is C10 alkyl; n=1, and R23 is an anticancer agent selected from the group consisting of gemcitabine, ara-C, 5-azacytidine, cladribine, fluclarabine, fluorodeoxyuridine, cytosine arabinoside and 6-mercaptopurine, wherein the methylene group of the phosphonate moiety is covalently linked to the oxygen atom of the 5xe2x80x2 hydroxyl group of a sugar moiety of R23.
The invention also includes a compound having the structure of Formula V: 
wherein,
R31 is (C1-C16)alkyl, branched alkyl, alkenyl, or alkynyl;
R32 is (C1-C16)alkyl, branched alkyl, alkenyl, or alkynyl;
X31 is O, S, or NHCxe2x95x90O;
X32 is O, S, or NHCxe2x95x90O;
X33 is xe2x80x94OH, xe2x80x94SH, or amino;
R33 is a therapeutic agent, and
wherein, each alkyl, branched alkyl, alkenyl, alkynyl, adenine, thymine, cytosine, guanine, pyrimidine, purine, hypoxanthine, inosine and uracil of R31, R32, and R33 can, optionally, be substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, nitro, trifluoromethyl, (C1-C8)alkyl, (C1-C8)alkoxy, aryl, and N(Ra)(Rb) wherein Ra and Rb are each independently selected from the group consisting of H and (C1-C8) alkyl.
In a preferred embodiment, R31 is (C6-C16)alkyl, branched alkyl, alkenyl or alkynyl; R32 is (C1-C8)alkyl, branched alkyl, alkenyl or alkynyl, and R33 is an anticancer agent selected from the group consisting of mitoxanthrone, methotrexate and CPT-11, and is covalently linked via an ester, amido or carbamate linkage to the xe2x80x94SH, OH or amino group of X33.
In one aspect, the compound is suspended in a pharmaceutically acceptable carrier and is present in an amount effective to combat a cancer in a mammal.
Preferably, the cancer is a cancer selected from the group consisting of a carcinoma, a sarcoma, a neuroblastoma, a leukemia, a lymphoma and a solid tumor.
In one aspect, the compound is present in an amount effective to facilitate delivery of a therapeutic agent to a mammalian cell.
Preferably, the therapeutic agent is an anticancer agent.
Preferably, the cell is in a mammal.
Preferably, the cell is a cell selected from the group consisting of a CNS cell and a lymphoid cell.
In one aspect, the CNS cell is an astrocyte or a glial cell.
In one embodiment, the compound is in the form of a pharmaceutically acceptable salt.
In one aspect, the compound is present in an amount effective to facilitate delivery of a therapeutic agent to a mammalian cell.
In one embodiment, the cell is in a mammal.
Preferably, the cell is a cell selected from the group consisting of a CNS cell and a lymphoid cell.
In one aspect, the compound is present in an amount effective to combat a cancer in a mammal.
In one embodiment, the compound in the pharmaceutically acceptable salt is present in an amount effective to facilitate delivery of a therapeutic agent to a mammalian cell.
Preferably, the therapeutic agent is an anticancer agent.
In one aspect, the cell is in a mammal.
In one embodiment, the cell is a cell selected from the group consisting of a CNS cell and a lymphoid cell.
In one aspect, the compound is present in an amount effective to combat a cancer in a mammal.
The invention also includes a drug delivery agent comprising a pharmaceutical composition. The composition comprises a compound of Formula III or a pharmaceutically acceptable salt thereof, in an amount effective to facilitate delivery of a therapeutic agent to a mammalian cell.
In one aspect, the therapeutic agent is an anticancer agent.
In another aspect, the cell is in a mammal.
Preferably, the cell is a cell selected from the group consisting of a CNS cell and a lymphoid cell.
The invention also includes a drug delivery agent comprising a pharmaceutical composition. The composition comprises a compound of Formula III or a pharmaceutically acceptable salt thereof, in an amount effective to combat a cancer in a mammal.
Preferably, the cancer is a cancer selected from the group consisting of a carcinoma, a sarcoma, a neuroblastoma, a leukemia, a lymphoma and a solid tumor.
The invention also includes a method of facilitating delivery of a therapeutic agent to a mammalian cell. The method comprises administering to the cell a pharmaceutical composition comprising a compound of Formula III or a pharmaceutically acceptable salt thereof, in an amount effective to facilitate delivery of the therapeutic agent to the cell.
In one aspect, the therapeutic agent is an anticancer agent.
In another aspect, the cell is in a mammal.
Preferably, the cell is a cell selected from the group consisting of a CNS cell and a lymphoid cell.
The invention also includes a method of facilitating delivery of a therapeutic agent to a cell. The method comprises administering to the cell a pharmaceutical composition comprising a compound of Formula III or a pharmaceutically acceptable salt thereof, in an amount effective to facilitate delivery of the therapeutic agent to the cell.
In one aspect, the cell is in a mammal.
In another aspect, the cell is a cell selected from the group consisting of a CNS cell and a lymphoid cell.
The invention also includes a method of combating a cancer in a mammal. The method comprises administering to the mammal a pharmaceutical composition comprising a compound of Formula III or a pharmaceutically acceptable salt thereof, in an amount effective to combat a cancer in the mammal.
In one aspect, the cancer is a cancer selected from the group consisting of a carcinoma, a sarcoma, a neuroblastoma, a leukemia, a lymphoma and a solid tumor.
The invention also includes a method of treating a disease in a mammal. The method comprises administering to the mammal a pharmaceutical composition comprising a compound of Formula III, or a pharmaceutically acceptable salt thereof, in an amount effective to facilitate delivery of a therapeutic agent to a cell in the mammal, thereby treating the disease.
In one aspect, the disease is a disease selected from the group consisting of a brain disease, a CNS disease, a lymphatic system disease, a reproductive system disease, a cardiovascular disease, a kidney disease and a liver disease.
The invention also includes a kit for combating a cancer in a mammal. The kit comprises a) a composition selected from the group consisting of a compound of Formula III, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising a compound of Formula III, and b) an instructional material.
The invention also includes a kit for facilitating delivery of a therapeutic agent to a mammalian cell. The kit comprises a) a composition selected from the group consisting of a compound of Formula III, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising a compound of Formula III, and b) an instructional material.
Preferably, the therapeutic agent is an anticancer agent.